Histone deacetylases (HDACs) are involved in the carcinogenesis by regulating cell proliferation, differentiation, and survival (Non Patent Literature 1 and 2). The inhibitors of HDACs (HDACi) have been shown to exhibit profound synergistic effects for cancer treatment when combined with other anticancer drugs (Non Patent Literature 2 and 3). The molecular mechanisms how this synergy is induced following the addition of HDACi, however, have not been fully understood.
Systematic in vitro studies revealed that HDACi can induce cell growth arrest, terminal differentiation, cell death and/or inhibition of angiogenesis in transformed cells without affecting normal cells (Non Patent Literature 2, 3 and 5). Based on these in vitro findings, several HDACi are currently being tested in clinical trials and one such inhibitor suberoylanilide hydroxamic acid (SAHA) has been approved by FDA for cutaneous T-cell lymphoma treatment (Non Patent Literature 4 and 5). HDACi have also shown synergistic or additive effects with a wide variety of anti-cancer reagents (Non Patent Literature 2 and 4). In addition, it is known that cytotoxicity of chemotherapeutic agents, including cisplatin, etoposide, 5-FU, and doxorubicin, is achieved in part by generation of reactive oxygen species (ROS) (Non Patent Literature 6 to 9). Consistent with these findings, alteration of antioxidant and its related gene expression modulate the resistance to chemotherapeutic drugs probably through its ROS scavenging ability (Non Patent Literature 10 to 13). This fact supports the findings that the induction of ROS by the chemotherapeutic drugs is important for cytotoxicity.